Chronic amphetamine intoxication causes a decreased threshold to drug-induced stereotyped development. In both man and animals, this effect is observed not only during intoxication but is observed to persist for months after drug withdrawal. Ellinwood (1974) has suggested that this "permanent" modification in the nigro-striatal dopamine (DA) system is an integral part of amphetamine and, perhaps, endogenous psychosis. We have developed an animal model which will enable us to study the mechanism of this phenomenon. Based on our preliminary observations as well as others, it appears logical to approach this by (1) further examination of the changes in the nigro-striatal DA synthesis, release, reuptake, metabolism and DA receptor activity that are responsible for the chronic amphetamine intoxication-induced decreased threshold; (2) in addition, behavioral experiments will be performed (using various DA synthesis inhibitors, receptor stimulators and blockers as well as DA releasing agents) to isolate those aspects of the DA system that are involved in this phenomenon; (3) to continue our studies to determine the role of synaptosomal membrane glycoproteins and phospholipids in DA release and reuptake mechanism. These data will then be incorporated into experiments designed to determine the mechanism of chronic drug-induced "permanent" changes in the DA system at the membrane structure level. Using this well-defined in vitro and in vivo model, our final goal is to establish how chronic drug treatment can alter membrane structure resulting in modification of synaptosomal function which finally leads to behavior abnormality. These data will be significant in furthering understanding of both neuronal plasticity and the etiology of drug-induced and functional psychosis.